Warburg Revisited: Regulation of Mitochondrial Metabolism by Voltage-Dependent Anion Channels in Cancer Cells

The bioenergetics of cancer cells is characterized by a high rate of aerobic glycolysis and suppression of mitochondrial metabolism (Warburg phenomenon). Mitochondrial metabolism requires inward and outward flux of hydrophilic metabolites, including ATP, ADP and respiratory substrates, through voltage-dependent anion channels (VDACs) in the mitochondrial outer membrane. Although VDACs were once considered to be constitutively open, closure of the VDAC is emerging as an adjustable limiter (governator) of mitochondrial metabolism. Studies of VDACs reconstituted into planar lipid bilayers show that tubulin at nanomolar concentrations decreases VDAC conductance. In tumor cell lines, microtubule-destabilizing agents increase cytoplasmic free tubulin and decrease mitochondrial membrane potential (Delta Psi(m)), whereas microtubule stabilization increases Delta Psi(m). Tubulin-dependent suppression of Delta Psi(m) is further potentiated by protein kinase A activation and glycogen synthase kinase-3 beta inhibition. Knockdown of different VDAC isoforms, especially of the least abundant isoform, VDAC3, also decreases Delta Psi(m), cellular ATP, and NADH/NAD(+), suggesting that VDAC1 and VDAC2 are most inhibited by free tubulin. The brake on mitochondrial metabolism imposed by the VDAC governator probably is released when spindles form and free tubulin decreases as cells enter mitosis, which better provides for the high ATP demands of chromosome separation and cytokinesis. In conclusion, tubulin-dependent closure of VDACs represents a new mechanism contributing to the suppression of mitochondrial metabolism in the Warburg phenomenon.